Hence, five silyl)oxymethyl)2 phenol was converted for the 3 derivative 50. Reduction to the corresponding aniline derivative followed by diazotization gave 3 phenoxy4trifluoromethoxybenzylic alcohol 51 in 52% yield. Oxidation of 51 with PCC in CH2Cl2 created the needed aldehyde 52. 3Morpholino and 3kinasesubstituted 4trifluoromethoxybenzaldehydes 55a?b have been synthesized following a equivalent sequence of response implemented from the synthesis of 40a?b. So, Buchwald coupling from the morpholine and piperidine with 2 phenyl)kinasedioxolane 54 and subsequent deprotection with the acetal afforded the expected aldehydes 55a?b in reasonable yields. Methyl5formyl2 benzoate 48 was synthesized from 42 in three procedures. Lithiation of 42 with secBuLi at ?78 ?C followed from the addition of methylchloroformate, subsequent deprotection of your TBS ether with TBAF and PCC mediated oxidation on the benzylic alcohol afforded 48.
Reductive amination of those aldehydes with amine seven was carried out in presence of NaCNBH3 in DMF containing AcOH to provide the nitroimidazole derivatives 56a?h in 15?fifty five percent yields. Dapivirine concentration Deprotection in the Omethoxymethyl ether 56d was carried out as described previously to provide 56i. Syntheses of one derivatives 59a?c with R3 modification getting 3F, 3OMe and 3OMOM substitutions was achieved by alkylation of alcohol 57 with the corresponding benzylic bromides 58a?b . Deprotection of your Omethoxymethyl ether in 59a was carried out making use of 6N HCl in THF to afford 59d. Results and Kinases R1 modifications: SAR of amides, ureas and tertiary amines Each benzyl ether and amine analogues of nitroimidazooxazines have already been shown to become equipotent towards M.
tuberculosis. The amenability in the benzylic amine in two permitted us to check out additional modifications from the series proven in Kinase 1. Nformylation lowered the two cellular action and compound libraries efficiency as being a substrate for Ddn by twofold compared to your mother or father compound two whereas Nacetylation from the amino group was detrimental to each MIC and MAC and reduced the catalytic efficiency of this as being a substrate for Ddn by nearly tenfold. The Npropionyl derivative 4b was insoluble and could not be evaluated. Naroyl amide derivatives behaved within a equivalent style with each benzoyl and chlorobenzoyl derivatives leading to compounds that had been significantly much less and potent towards replicating and nonreplicating Mtb.
We also explored one urea derivative but did not elaborate around the series after the observation that lowering the basicity of nitrogen resulted in significantly less potent compounds. The catalytic activity from the basic amide substituted molecules as substrates for your Ddn enzyme, measured as kcat/KM for reoxidation of diminished F420, was usually reduced than that within the 1, nevertheless, inside of this group there was normally only a weak correlation involving enzymatic exercise and MIC.